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BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low‐intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open‐label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1‐hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1‐hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109/L and ≥10 × 109/L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1‐year survival. The trial is registered at ClinicalTrials.gov (NCT01303796).ResultsBetween October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109/L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017).ConclusionsThe regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109/L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Background: Prospective studies evaluating second-look imaging of meniscus root repair using a transtibial pull-out technique are limited; therefore, optimal surgical indications and the technique for meniscus root repair remain uncertain. Hypothesis: It was hypothesized that there would be a high rate of healing, improvement in meniscal extrusion, and prevention of articular cartilage degeneration and subchondral bone abnormalities after meniscus root repair. Study Design: Case series; Level of evidence, 4. Methods: Consecutive patients undergoing transtibial root repair were prospectively enrolled at 2 orthopaedic centers between March 2017 and January 2019. Pre- and postoperative magnetic resonance imaging (MRI) scans were reviewed by a musculoskeletal radiologist in a blinded fashion for meniscal healing, quantification of extrusion, articular cartilage grade, subchondral bone changes, and coronary/meniscotibial ligament abnormalities. Given persistent extrusion observed on postoperative MRI scans, an additional 10 patients gave consent and were enrolled for immediate (before weightbearing) postoperative MRI scans. Results: A total of 45 patients (16 male, 29 female; mean ± standard deviation age, 42.3 ± 12.9 years; body mass index, 31.6) were prospectively enrolled in the study; there were 47 meniscus root repairs: 29 medial and 18 lateral (2 with both). Postoperative MRI was obtained at an average of 6.3 months (range, 5.1-8 months); 98% of meniscal repairs had evidence of healing. Mean extrusion increased significantly, from 1.9 ± 1.5 mm preoperatively to 2.6 ± 1.4 mm postoperatively ( P = .03). There was no significant progression of chondromalacia grade, subchondral edema, insufficiency fracture, subchondral cysts, or subchondral collapse. In the additional 10-patient cohort, the mean preoperative extrusion (1.6 ± 1.2 mm) was not significantly different from that immediately postoperatively (2.0 ± 1.0 mm; P = .23). Conclusion: Prospective MRI analysis of transtibial meniscus root repair confirmed a high rate of meniscal healing and no observable progression of cartilage degeneration or subchondral bone abnormalities at the short-term follow-up. However, meniscal extrusion worsened in the first 6 months after surgery. Registration: NCT03037242 ( ClinicalTrials.gov identifier).

Abstract Aims The aim of this article was to compare rates of all-cause death at 10 years following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in patients with or without diabetes. Methods and results The SYNTAXES study evaluated up to 10-year survival of 1800 patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to receive either PCI or CABG in the SYNTAX trial. Ten-year all-cause death according to diabetic status and revascularization strategy was examined. In diabetics (n = 452), the risk of mortality was numerically higher with PCI compared with CABG at 5 years [19.6% vs. 13.3%, hazard ratio (HR): 1.53, 95% confidence interval (CI): 0.96, 2.43, P = 0.075], with the opposite seen between 5 and 10 years (PCI vs. CABG: 20.8% vs. 24.4%, HR: 0.82, 95% CI: 0.52, 1.27, P = 0.366). Irrespective of diabetic status, there was no significant difference in all-cause death at 10 years between patients receiving PCI or CABG, the absolute treatment difference was 1.9% in diabetics (PCI vs. CABG: 36.4% vs. 34.5%, difference: 1.9%, 95% CI: −7.6%, 11.1%, P = 0.551). Among insulin-treated patients (n = 182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%, difference: 8.2%, 95% CI: −6.5%, 22.5%, P = 0.227). Conclusions The treatment effects of PCI vs. CABG on all-cause death at 10 years in patients with 3VD and/or LMCAD were similar irrespective of the presence of diabetes. There may, however, be a survival benefit with CABG in patients with insulin-treated diabetes. The association between revascularization strategy and very long-term ischaemic and safety outcomes for patients with diabetes needs further investigation in dedicated trials. Trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972 and SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

Abstract Background Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. Methods Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in the phase 1 clinical trial. Results PDX tumors exposed to different doses of adavosertib revealed intra- and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient’s response to adavosertib. Conclusions The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to preclinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice.

Abstract OBJECTIVES This study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study. METHODS The present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed. RESULTS Of the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55–0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44–0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles. CONCLUSIONS In the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy. Trial registration SYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.

Background: In recent years, the prevalence of medial ulnar collateral ligament injuries has increased in throwers of all ages and skill levels. The motusBASEBALL sensor possesses an inertial measurement unit (IMU) that has been developed and applied to the throwing arm to allow for measurements of several objective parameters, which may prove beneficial for monitoring, rehabilitation, and injury prevention in the throwing athlete. However, the reliability, consistency, and validity of the IMU have not been independently assessed. Purpose: To evaluate the reliability, consistency, and validity of the motusBASEBALL sensor compared with the historic gold standard of marker-based motion capture. Study Design: Controlled laboratory study. Methods: A total of 10 healthy male baseball athletes with varsity-level high school experience volunteered to participate in this study. Participants were fitted with 37 retroreflective markers for motion capture and the motusBASEBALL IMU sensor. Participants threw 5 fastballs at maximum effort, with measurements recorded simultaneously by motion capture and the IMU. Arm slot, arm speed, arm stress, and shoulder rotation were measured and compared. Results: Of the 4 metrics generated by the IMU, significant differences were found for 3 of the throwing metrics compared with motion capture including arm slot (5.0°± 6.1°; P = .037), elbow varus torque (9.4 ± 12.0 N·m; P = .037), and shoulder rotation (6.3°± 6.1°; P = .014). Arm speed did not demonstrate a statistically significant difference (29.2 ± 96.8 rpm; P = .375). The IMU consistently underreported pitching performance values. Shoulder rotation exhibited excellent reliability with <5° of error, and arm slot demonstrated good reliability with <10° of error. Arm stress and arm speed were less reliable. Conclusion: The IMU was not accurate or valid for arm slot, arm stress, and shoulder rotation compared with marker-based motion capture. It was relatively accurate for arm speed. Despite its lack of validity, it was consistent and reliable for arm speed and shoulder rotation and relatively reliable for arm slot and arm stress. Caution should be used when comparing values provided by this IMU to the gold standard of marker-based motion capture. Clinical Relevance: IMU technology has potential to be used in monitoring, rehabilitation, and injury prevention in throwing athletes if valid. This study demonstrates that the values provided by the IMU should not be considered equivalent to those generated by the gold standard of marker-based motion capture; however, there may still be a role for this technology when relying on its internal consistency for intrathrower comparisons and tracking.

Objectives: Meniscus root tears are increasingly being recognized. Meniscus extrusion has previously been associated with medial root tears; however, the relationship between secondary meniscus restraints, such as the meniscotibial (MT) ligament, extrusion, and root tears has yet to be formally evaluated. The purpose of this study was to better understand the association between MT ligament competence, medial meniscus extrusion, and medial meniscus posterior root tears (MMPRT), as well as to determine the progression of meniscus extrusion over time. Methods: Serial MRI’s from our institution were reviewed for patients who showed evidence of medial meniscus extrusion and MMPRT on at least one of 2+ available MRI’s. All patients were symptomatic at the time of diagnosis. All MRI’s were analyzed independently by two board-certified musculoskeletal radiologists. MT ligament disruption, medial meniscus extrusion, and MMPRT presence was recorded for each MRI. The time between MRI’s, presence of insufficiency fractures, and Outerbridge classification for the medial femur and tibia were also evaluated. Results: 27 knees in 26 patients were included in this study, with a total of 63 MRI’s analyzed (21 knees with 2 MRI’s, 3 with 3 MRI’s, and 3 with 4 MRI’s). All patients demonstrated clear medial meniscus extrusion and meniscotibial ligament disruption prior to the subsequent development of MMPRTs (p < 0.001). Mean extrusion at the time of initial MRI was 3.3 ± 1.1 mm, and increased significantly to 5.5 ± 1.8 mm at the time of first imaging with an identified MMPRT (p < 0.001). The average time between initial MRI and the first identification of MMPRT on a later MRI was 1.7 ± 1.6 years. Conclusions: In a sample of 27 symptomatic knees with serial MRI’s both before and after MMPRT diagnosis, all patients demonstrated MT ligament disruption and associated meniscus extrusion prior to the development of subsequent medial meniscus root tears. These findings suggest that MT ligament disruption and medial meniscus extrusion represent early and predisposing events contributing to MMPRT. Therefore, this provides a possible explanation of why meniscus extrusion is not corrected with medial meniscus root repair.

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.